Targeting Integrins in Lung Cancer

靶向肺癌中的整合素

• 批准号: 10016907
• 负责人: Tianhong Li
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10016907
• 关键词: Affinity; Antibody Therapy; Antitumor Response; Archives; Biological Assay; Biological Markers; Biopsy; Blood; Blood Banks; Blood specimen; Body Fluids; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Patient; Carcinoma; Case Study; Cell Death; Cells; Cessation of life; Clinical; Clonal Evolution; Complex; Detection; Diagnosis; Diagnostic; Diagnostic tests; Disease; Distant Metastasis; Drug Delivery Systems; Drug Targeting; Drug resistance; Epidermal Growth Factor Receptor; Equilibrium; FDA approved; Flow Cytometry; Fluorescent in Situ Hybridization; General Population; Genes; Genomics; Genotype; Goals; Growth; Guidelines; Hot Spot; Image; Immune; Immune checkpoint inhibitor; Immune system; Immunodiagnostics; Immunohistochemistry; Immunologic Markers; Immunotherapy; In Vitro; Individual; Institutional Review Boards; Integrin alpha3beta1; Integrin alpha4beta1; Integrins; Life; Ligands; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Malignant Pleural Effusion; Malignant neoplasm of lung; Membrane; Meta-Analysis; Modality; Molecular; Molecular Abnormality; Molecular Target; Monitor; Mutation; National Comprehensive Cancer Network; Neoplasm Circulating Cells; Non-Small-Cell Lung Carcinoma; Oncogenes; Operative Surgical Procedures; Patient Care; Patients; Peptides; Phase; Plasma; Pleural effusion disorder; Polymerase Chain Reaction; Process; Proteins; Protocols documentation; Resources; Sampling; Selection for Treatments; Shapes; Specificity; Specimen; Surface; T-Cell Receptor; Testing; Thoracentesis; Time; Tumor Specific Peptide; Tumor-Derived; Tumor-infiltrating immune cells; Veterans; base; cancer cell; cancer immunotherapy; cancer therapy; cancer type; checkpoint therapy; clinical application; clinical decision-making; companion diagnostics; cost; diagnostic platform; drug-sensitive; effective therapy; exosome; immune checkpoint blockade; improved; improved outcome; in-vitro diagnostics; innovation; liquid biopsy; microvesicles; military veteran; minimally invasive; molecular diagnostics; molecular marker; molecular targeted therapies; multiplex assay; neoplastic cell; new technology; next generation sequencing; novel; novel diagnostics; novel therapeutic intervention; patient population; peripheral blood; personalized medicine; precision medicine; precision oncology; programmed cell death ligand 1; programmed cell death protein 1; programs; resistance mutation; response; specific biomarkers; success; targeted treatment; treatment response; tumor; tumor DNA; tumorigenesis

Lung cancer is the most common cause of cancer-related deaths in US veterans and worldwide. Molecularly targeted therapy and immunotherapy are two recent major breakthroughs in lung cancer treatment that have been shown to extend life and increase cure, but each of them benefits ~20% of non-small cell lung cancer (NSCLC) patients. Novel therapeutic strategies are needed to identify new treatment targets and develop and validate the assays that select the appropriate patients for molecularly targeted therapy and cancer immunotherapy and monitor antitumor responses. We have recently generated and characterized high-affinity peptide ligands for targeting tumor-specific and lymphocyte-specific integrins on the surface of multiple epithelial cancer types including NSCLC and microvesicle exosomes derived from the membranes of specific cancer or immune cells. We hypothesize that these high affinity peptide ligands can be used to improve the sensitivity of detecting tumor- and immune cell-specific biomarkers in lung cancer patients. The overall objective of this proposal is to develop easily operable, low cost, sensitive, multiplex assays to improve the sensitivity of current molecular and immune biomarker tests, in a single blood draw or thoracentesis for clinical decision-making in cancer treatment selection and monitoring. We will use biofluid samples collected from patients with advanced NSCLC under IRB-approved protocol to optimize our novel in vitro diagnostic platforms. In specific aim 1, we develop an assay for sensitive detection and enrichment of tumor cells from malignant body fluids of NSCLC patients using LXY30 (for α3β1 integrin). In specific aim 2, we will develop a novel in vitro platform for rapid and simple isolation of tumor-specific exosomes yielding high quantity and quality tumor DNA to increase the success of clinical molecular biomarker assays. In specific aim 3, we will develop a novel in vitro platform for rapid and simple isolation of functional immune cells in the blood from NSCLC patients for flow cytometry, T cell receptor diversity, and single cell genomic characterization. We anticipate that the clinical application of our novel, integrated, simple, low cost, in vitro diagnostic platform in a serial noninvasive “liquid biopsy” can select the most effective treatment for cancer patients in real time and thus has great potential to advance individual cancer patient care towards the goal of precision medicine.

肺癌是美国退伍军人和世界各地与癌症相关的死亡最常见的原因。从分子上讲 靶向治疗和免疫治疗是肺癌治疗的两个最新重大突破，它们已经 已被证明可以延长生命和提高治愈率，但每种药物对大约20%的非小细胞肺癌患者都有好处 (非小细胞肺癌)患者。需要新的治疗策略来确定新的治疗目标并开发和 验证选择合适的患者进行分子靶向治疗和癌症的分析 免疫治疗和监测抗肿瘤反应。我们最近产生了并表征了高亲和力 靶向肿瘤特异性整合素和淋巴细胞特异性整合素的多肽配体 上皮癌类型包括非小细胞肺癌和来自特定细胞膜的微囊外体 癌症或免疫细胞。我们假设这些高亲和力的多肽配体可以用来改善 肺癌患者肿瘤和免疫细胞特异性生物标志物检测的敏感性。整体而言 该方案的目的是开发易于操作、低成本、灵敏的多重检测方法，以提高 临床一次抽血或胸腔穿刺术中当前分子和免疫生物标记物检测的敏感性 癌症治疗选择和监测中的决策。我们将使用从 根据IRB批准的方案治疗晚期非小细胞肺癌患者，以优化我们的新体外诊断 站台。在特定目标1中，我们开发了一种灵敏的检测和浓缩肿瘤细胞的方法 非小细胞肺癌患者恶性体液LXY30(α-3-β-1整合素)在具体目标2中，我们将制定一项 一种新的快速、简便的肿瘤特异性外切体的体外分离平台 高质量的肿瘤DNA，提高临床分子生物标记物检测的成功率。在具体目标3中，我们将 建立一种新的快速、简便的血液免疫细胞体外分离平台 对非小细胞肺癌患者进行流式细胞术、T细胞受体多样性和单细胞基因组特征分析。我们 预计我们的新型、集成、简单、低成本的体外诊断平台在临床上的应用 连续式无创性“液体活检术”可实时为癌症患者选择最有效的治疗方案 从而极大地促进了癌症患者个体化护理向精准医学的目标迈进。